Atherosclerosis, a disease characterized by occlusion of the arteries, is triggered by the build-up of oxidized low density lipoprotein (oxLDL) in vascular intima (Li, et al., The macrophage foam cell as a target for therapeutic intervention. Nat Med 2002, 8 (11), 1235-1242). The oxLDL accumulation generates an inflammatory response, resulting in the recruitment of circulating monocytes, followed by their differentiation into macrophages, resulting in the upregulation of macrophage scavenger receptors (Yoshimoto, et al., Growth stimulation and epidermal growth factor receptor induction in cyclooxygenase-overexpressing human colon carcinoma cells. Adv Exp Med Biol 2002, 507, 403-7). The uptake of oxLDL is mediated by these scavenger receptors, namely scavenger receptor A (SR-A) and cluster of differentiation 36 (CD36) (Goldstein, J. L.; et al., Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA 1979, 76 (1), 333-7; Podrez, E. A.; et al., Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J Clin Invest 2000, 105 (8), 1095-108; de Winther, M. P.; et al., Macrophage scavenger receptor class A: A multifunctional receptor in atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 2000, 20 (2), 290-7), leading to unregulated cholesterol accumulation and foam cell formation, a key characteristic of the onset of atherogenesis (Brown, M. S.; Goldstein, J. L., Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annual review of biochemistry 1983, 52, 223-61; Steinberg, D., Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem 1997, 272 (34), 20963-6).
To date, cholesterol-lowering therapies (i.e., statins) are the most common methods for management of the long-term effects of atherosclerosis. These drugs indirectly ameliorate the cascade of atherosclerosis by decreasing cholesterol synthesis; however, the ultimate impact on the deposition of oxLDL in the blood vessel walls has not been clearly established. A more direct and promising approach in the treatment and prevention of atherosclerosis involves designing functional inhibitors against scavenger receptors to abrogate uncontrolled oxLDL uptake (Boullier, A.; et al., Phosphocholine as a pattern recognition ligand for CD36. J Lipid Res 2005, 46 (5), 969-976; Yoshiizumi, K.; et al., 2,4-Bis(octadecanoylamino)benzenesulfonic acid sodium salt as a novel scavenger receptor inhibitor with low molecular weight. Bioorg Med Chem Lett 2004, 14 (11), 2791-2795; Guaderrama-Diaz, M.; et al., Control of scavenger receptor-mediated endocytosis by novel ligands of different length. Mol Cell Biochem 2005, 271 (1-2), 123-132; Broz, P.; et al., Cell targeting by a generic receptor-targeted polymer nanocontainer platform. J Control Release 2005, 102 (2), 475-488).
Nanoscale amphiphilic macromolecules (AMs) capable of inhibiting oxLDL uptake through competitive inhibition of SRA and CD36 scavenger receptors in IC21 macrophage cells have been reported (Chnari, E.; et al., Biomacromolecules 2006, 7, 1796-1805). Comprised of a mucic acid backbone, four aliphatic chains, and a poly(ethylene glycol) (PEG) tail, these biocompatible AMs form nanoscale micelles in aqueous media at relatively low critical micelle concentrations (10−7 M). There remains a need for therapeutic agents that treat athereosclerosis and agents that do so through alternative mechanisms of action.